Delayed protective effect of chronic variable stress on optic tract axonal degeneration after experimental TBI

Of the 2.8 million individuals who seek medical attention for traumatic brain injury (TBI) each year, nearly 300,000 require hospitalization, with up to 60% of these needing intensive care. Intensive care treatment of TBI involves stressful events such as sleep disruption, noise, and painful procedures, potentially leading to chronic stress in patients undergoing such treatment. Given that physiologic stress can exacerbate neuroinflammation and impair normal neural function, we hypothesized that chronic variable stress (CVS) following TBI would exacerbate behavioral and pathological outcomes. We tested this hypothesis by subjecting adolescent male mice to blunt TBI, followed by two weeks of CVS or control conditions. We assessed brain pathologic responses to injury 2-, 5-, 20-, and 28-weeks post-injury. We found chronic optic tract degeneration by Fluoro-jade B staining in TBI groups. Unexpectedly, CVS+TBI mice did not show evidence of optic tract axon degeneration 20 weeks after injury, but did at the other time points. CVS led to increased microglial phagocytic markers early after injury, regardless of TBI status, and TBI led to increased microglial phagocytic markers in a delayed fashion as well. Notably, microglial phagocytosis markers were not elevated in TBI+CVS groups compared to TBI only groups 20 weeks post-injury. There was no effect of TBI or CVS on behavioral measures taken at the end of CVS. These findings suggest a delayed, but not permanent, protective effect on axonal degeneration after TBI, potentially related to altered microglial and astrocytic phagocytic activity.